PROJECT SUMMARY Autism spectrum disorders are among the most common neurodevelopmental disorders, affecting 1 in 42 boys and 1 in 189 girls, and present an urgent and growing public health challenge. Numerous autism risk genes have been identified, yet it is not clear how mutations in single genes cause the diverse behavioral alterations in autism, including pervasive sleep disturbances and deficits in learning and cognition. We hypothesize that, at least for a subset of autism risk genes, the dysregulation of multiple downstream molecular pathways, some during neuronal development and others in the more mature brain, underlie distinct behavioral aspects of autism. Because many autism risk genes are highly conserved, animal models such as the fruit fly Drosophila represent an opportunity to leverage powerful genetic tools to dissect mechanisms underlying autism. Our studies in Drosophila demonstrated a link between the Cullin-3 (Cul3) ubiquitin ligase, the BTB adaptor protein Insomniac (Inc), and the regulation of sleep?wake cycles. Our proposed research will utilize genetic manipulations in Drosophila to elucidate mechanisms and substrates underlying the impact of Cul3-Inc complex on sleep and other behaviors. By improving our understanding of how alterations in cellular ubiquitination pathways contribute to sleep dysfunction and cognitive deficits, our studies may ultimately provide insight into the etiology of autism and other neurological disorders.